The difficulty of forming interploidy or interspecies hybrids of plants demonstrates the importance of matched parents in reproduction. "Unbalanced" parental contributions cause seed failure. Interestingly, balance is a genetic trait and not only a consequence of genome dosage, as certain diploids can be better matched with tetraploid species than with other diploid species. We hypothesize that regulation of chromatin and growth are dosage-sensitive processes that affect the success of plant hybridization. This hypothesis is supported by the following preliminary observations: Arabidopsis parents with identical genotypes produce dead or viable hybrid seeds depending on the parental genomic ratio. Seeds from interspecific crosses display dosage-dependent derepression of the heterochromatic repeat ATHILA, and of the imprinted, paternally- expressed, transcription factor PHE1. Decreased activity of PHE1 suppresses death in interspecific crosses. Using genetic variation in parental dosage potential, we have characterized the genetics of interploidy and interspecies hybridization finding that both are controlled by few QTL. Maternal sensitivity to interploidy crosses responds to the transcription regulator TTG2, which acts in maternal tissue to modulate endosperm growth. Decreased activity of TTG2 results in seed survival and is likely to explain an observed major effect QTL. Based on these results, we propose to: 1. Determine the molecular basis of QTL affecting interspecific and interploidy postzygotic incompatibility. 2. Investigate the transcriptional consequences of the fusion of mismatched gametes in both interspecific and interploidy matings. 3. Investigate the causes and consequences of ATHILA and PHERES1 misexpression and the developmental consequences of incompatibility. The proposed research will fill a lacuna in our understanding of factors governing postzygotic compatibility in plants and help address the function of chromatin and growth regulators as dosage sensitive components. Although aneuploidy, the unbalanced dosage of genomic elements, is associated with cancer and causes several genetic diseases such as Down Syndrome, it is difficult to study its molecular basis in humans. The plant Arabidopsis provides the opportunity to dissect dosage determinants in a model eukaryote. The knowledge gained in this study may help understand dosage-related diseases and possibly help in their prevention and treatment.